title: Deletion in the N-terminal half of olfactomedin 1 modifies its interaction with synaptic proteins and causes brain dystrophy and abnormal behavior in mice.
abstract: Olfactomedin 1 (Olfm1) is a secreted glycoprotein that is preferentially expressed in neuronal tissues. Here we show that deletion of exons 4 and 5 from the Olfm1 gene, which encodes a 52 amino acid long region in the N-terminal part of the protein, increased neonatal death and reduced body weight of surviving homozygous mice. Magnetic resonance imaging analyses revealed reduced brain volume and attenuated size of white matter tracts such as the anterior commissure, corpus callosum, and optic nerve. Adult Olfm1 mutant mice demonstrated abnormal behavior in several tests including reduced marble digging, elevated plus maze test, nesting activity and latency on balance beam tests as compared with their wild-type littermates. The olfactory system was both structurally and functionally disturbed by the mutation in the Olfm1 gene as shown by functional magnetic resonance imaging analysis and a smell test. Deficiencies of the olfactory system may contribute to the neonatal death and loss of body weight of Olfm1 mutant. Shotgun proteomics revealed 59 candidate proteins that co-precipitated with wild-type or mutant Olfm1 proteins in postnatal day 1 brain. Olfm1-binding targets included GluR2, Cav2.1, teneurin-4 and Kidins220. Modified interaction of Olfm1 with binding targets led to an increase in intracellular Ca(2+) concentration and activation of ERK1/2, MEK1 and CaMKII in the hippocampus and olfactory bulb of Olfm1 mutant mice compared with their wild-type littermates. Excessive activation of the CaMKII and Ras-ERK pathways in the Olfm1 mutant olfactory bulb and hippocampus by elevated intracellular calcium may contribute to the abnormal behavior and olfactory activity of Olfm1 mutant mice.
authors.affiliation: Ganglion Cell Biology Section, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, NIH, Bethesda, MD 20892, USA. Electronic address: nakayan@nei.nih.gov.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakaya
authors.forename: Afia
authors.initials: A
authors.lastname: Sultana
authors.forename: Jeeva
authors.initials: J
authors.lastname: Munasinghe
authors.forename: Aiwu
authors.initials: A
authors.lastname: Cheng
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Stanislav I
authors.initials: SI
authors.lastname: Tomarev
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D005091:Exons / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D040901:Proteomics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion
chemical_list: D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C081451:olfactomedin
keywords: AMPA receptor; Anxiety behavior; Cell signaling; MRI; Magnetic resonance imaging; Mouse; Neurobiology; Olfactomedin 1; Olfactory defects; Olfm1; Olfm1 knockout; Olfm1-KO; Proteomics; Q-PCR; Quantitative RT-PCR